Antagonists are substances that tend to nullify the action of another substance (the agonist). Antagonists of narcotics are believed to function by binding competitively to the opioid receptor, thereby preventing occupation of the receptor by the (therapeutic) agonist. At least four types of opioid receptors have been identified in the central nervous system - mu, kappa, sigma, and delta. The affinity of a particular antagonist for each receptor may not be equal. In general, antagonists have a greater affinity for the mu receptor. Antagonist compounds may act centrally or peripherally, may act at specific opiate receptor sites or through a non-specific analeptic mechanism or through a neurotransmitter system.
A number of patents disclose certain N-heterocyclic-N-(4-piperidinyl)amides having therapeutic activity. For example, U.S. Pat. No. 4,546,105, issued to Effland et al. and assigned to Hoechst-Roussel Pharmaceuticals Inc., discloses N-pyrrolyl-N-(4-piperidinyl)amine and amide compounds useful as analgesics. An article entitled "Synthesis and Analgesic Activity of Derivatives of Fentanyl" by Zhu Youcheng et al., printed in Acta Pharmaceutica Sinica, Vol. XVI, No. 3, pp. 199-209 March, 1981, discloses the synthesis of substituted N-aryl-N-(4-piperidinyl)amide compounds which possess morphine-like activities. Sigmar Grossmann et al., in Arch. Pharm. (Weinheim) 311, pp. 1010-1015 (1978), disclose the preparation of substituted N-pyridine analogues of fentanyl which possess analgesic activity. Frans Janssens et al., in Journal of Medicinal Chemistry. Vol. 28, No. 12, pp. 1925-1933, 1934-1943, 1943-1947 (1985), disclose the synthesis of masked N-substituted-N-(4-piperidinyl)amides which possess antihistaminic properties.
Naloxone, also known as 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one, has gained widespread use in anesthesia as an antagonist for opioid induced respiratory depression and sedation, (Editorial, British Journal of Anesthesia, Vol. 57, No. 6, pp. 547-549 June, 1985. Naloxone is mainly used to terminate undesirable opioid effects during the immediate post operative period.
The use of naloxone gas an anesthesia antagonist has disadvantages. These disadvantages include, for example, undesirable side effects such as ventricular dysrhythmia, hypertension and pulmonary edema following intravenous administration of the drug. Naloxone also tends to reverse or antagonize the desirable analgesic effects of opioids.
Accordingly there is a need for a safe drug which will antagonize the undesirable effects of opioids such as respiratory and cardiac depression without antagonizing the desirable effects such as analgesia and anesthesia. The present invention provides such compounds, methods by which these compounds may be prepared, and pharmaceutical compositions and methods employing such compounds.